This invention relates to pyridopyrimidines and 4-aminopyrimidines that inhibit cyclin-dependent kinase and growth factor-mediated kinase enzymes, and as such are usefull to treat cell proliferative disorders such as atherosclerosis, restenosis, and cancer.
Cell cycle kinases are naturally occurring enzymes involved in regulation of the cell cycle (Meijer L., xe2x80x9cChemical Inhibitors of Cyclin-Dependent Kinasesxe2x80x9d, Progress in Cell Cycle Research, 1995;1:351-363). Typical enzymes include the cyclin-dependent kinases (cdk) cdk1, cdk2, cdk4, cdk5, cdk6, and wee-1 kinase. Increased activity or temporally abnormal activation of these kinases has been shown to result in development of human tumors and other proliferative disorders such as restenosis. Compounds that inhibit cdks, either by blocking the interaction between a cyclin and its kinase partner, or by binding to and inactivating the kinase, cause inhibition of cell proliferation, and are thus useful for treating tumors or other abnormally proliferating cells.
Several compounds that inhibit cdks have demonstrated both preclinical and clinical anti-tumor activity. For example, flavopiridol is a flavonoid that has been shown to be a potent inhibitor of several types of breast and lung cancer cells (Kaur, et al., J. Natl. Cancer Inst., 1992;84:1736-1740; Int. J. Oncol., 1996;9:1143-1168). The compound has been shown to inhibit cdk2 and cdk4. Olomoucine [2-hydroxyethylamine)-6-benzylamine-9-methylpurine] is a potent inhibitor of cdk2 and cdk5 (Vesely, et al., Eur. J. Biochem., 1994;224:771-786), and has been shown to inhibit proliferation of approximately 60 different human tumor cell lines used by the National Cancer Institute (NCI) to screen for new cancer therapies (Abraham, et al., Biology of the Cell, 1995;83:105-120).
Despite the progress that has been made, the search continues for small molecular weight compounds that are orally bioavailable and useful for treating a wide variety of human tumors and other proliferative disorders such as restenosis and atherosclerosis.
This invention provides pyridopyrimidines and 4-aminopyrimidines that are useful for treating cell proliferative disorders, such as cancer, atherosclerosis, restenosis, psoriasis, and endometriosis. We have discovered a group of 7,8-dihydro-2-(amino and thio)-7-(oxo, thio, or imino)-pyrido[2,3-d]pyrimidines and 4-aminopyrimidines that are potent inhibitors of cyclin-dependent kinases (cdks). The compounds are readily synthesized and can be administered by a variety of routes, including orally and parenterally, and have little or no toxicity. The compounds of the invention are members of the class of compounds of Formula I: 
and Formula II: 
wherein:
W is NH, S, SO, or SO2;
R1 and R2 include alkyl, cycloalkyl, substituted alkyl, and substituted cycloalkyl;
R3 includes hydrogen, alkyl, and halogen;
X is O, S, or NH;
R8 and R9 independently are hydrogen, alkyl, alkoxy, halo, amino, and the like;
and pharmaceutically acceptable salts thereof.
This invention also provides pharmaceutical formulations comprising a compound of Formula I or II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.
Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdk2, cdc2, and cdk4. Some of the compounds of the present invention also inhibit growth factor mediated tyrosine kinases including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). As inhibitors of cyclin-dependent, as well as growth factor-mediated, tyrosine kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle cell proliferation associated with atherosclerosis, and postsurgical vascular stenosis and restenosis in mammals.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by cellular proliferation. The method entails inhibiting proliferation of tumorigenic cells of epithelial origin and vascular smooth muscle proliferation, and/or cellular migration by administering a therapeutically effective amount of a compound of Formula I and/or II to a subject in need of treatment.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by DNA tumor viruses such as herpes viruses.
We have discovered a new class of compounds that are potent inhibitors of cyclin-dependent kinases (cdks) and are useful agents for treating subjects suffering from diseases caused by abnormal cell proliferation. Compounds within the scope of the present invention are inhibitors of the cyclin-dependent kinases such as cdc2, cdk2, and cdk4. As inhibitors of cyclin-dependent kinases, the compounds of the instant invention are useful in controlling proliferative disorders such as cancer, psoriasis, vascular smooth muscle proliferation associated with atherosclerosis, postsurgical vascular stenosis, and restenosis in mammals.
The compounds of the invention comprise those of Formula I: 
and the pharmaceutically acceptable salts thereof,
wherein:
the dotted line represents an optional double bond;
W is NH, S, SO, or SO2;
X is either O, S, or NH;
R1 and R2 are independently selected from the group consisting of H, (CH2)nAr, (CH2)nheteroaryl, (CH2)nheterocyclyl, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein n is 0, 1, 2, or 3, and the (CH2)nAr, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by up to 5 groups selected from NR4R5, N(O)R4R5, NR4R5R6Y, alkyl, phenyl, substituted phenyl, (CH2)nheteroaryl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, aldehyde, nitrile heteroaryloxy, T(CH2)mQR4, 
C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4, T(CH2)mC(O)NR4NR5, or T(CH2)mCO2R4 wherein each m is independently 1-6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, and Q is O, S, NR5, N(O)R5, or NR5R6Y;
R3 is H, alkyl, halogen, NO2, NR4R5, COOR4, OR4, CN, or CONR4R5;
R4 and R5 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)nAr, C3-C10 cycloalkyl, heterocyclyl, and heteroaryl, or R4 and R5 together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur;
R4 and R5 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted alkyl, C3-C10 cycloalkyl, C2-C6 heterocyclyl, and C2-C6 heteroaryl, or R4 and R5 together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur; optionally substituted with alkyl, T(CH2)mQR4xe2x80x2, C(O)T(CH2)mQR4xe2x80x2, T(CH2)mCO2R4xe2x80x2, (CH2)mQR4xe2x80x2, T(CH2)mCONR4xe2x80x2R5xe2x80x2 wherein m is 1-6, T is O, S, NR4xe2x80x2, N(O)R4xe2x80x2, or CR4xe2x80x2R5xe2x80x2, and Q is O, S, NR5xe2x80x2, or N(O)R5xe2x80x2;
R4xe2x80x2 and R5xe2x80x2 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted alkyl, C3-C10 cycloalkyl, C2-C6 heterocyclyl, and C2-C6 heteroaryl;
R6 is alkyl;
R8 and R9 independently are H, C1-C3alkyl, NR4R5, N(O)R4R5, NR4R5R6Y, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, or NO2; and
Y is a halo counter-ion.
An especially preferred group of compounds of Formula I have the above formula wherein X is O.
Another preferred group of compounds are those wherein W is NH.
A preferred group of compounds of Formula I have the above formula wherein X is O, and R3 is CH3 or H. In an especially preferred group of compounds, X is O, and R3 is H.
Also preferred are compounds of Formula I wherein R8 and R9 both are hydrogen.
Another preferred group of compounds of Formula I have the above formula wherein X is O, and R2 is Et, Pr, i-Pr, i-Bu, i-pentyl, or cycloalkyl. In an especially preferred group of compounds, X is O and R2 is i-Pr or i-pentyl.
In yet another preferred group of compounds of Formula I, X is O, and R1 is phenyl. Another preferred group of compounds of Formula I have one or more of the following structural features: X is O, and there is a double bond between C5 and C6, R1 is phenyl, optionally substituted with 4-piperidinyl (with or without substitution), 4-(2-diethylaminoethoxy) or 4-(4-methyl piperazin-1-yl); and R2 is a branched alkyl or cycloalkyl, including but not limited to isopropyl, cyclopentyl, cyclohexyl, or norbornyl. In an especially preferred group of compounds, X is O, and R1 is phenyl substituted with hydroxy, alkoxy, NR4R5, or T(CH2)mQR4, where R4 and R5, T, m, and Q all are as defined above. In an even more preferred group of compounds, X is O, and R1 is phenyl substituted with NR4R5 or T(CH2)mQR4, where R4 and R5, T, m, and Q all are as defined above.
Another preferred group of compounds of Formula I are those wherein X is NH.
The most preferred compounds of the present invention have the formula: 
where R2 is as defined above, and Ar is phenyl, substituted phenyl, or heteroaryl. Ideally, R2 is alkyl such as ethyl, isopropyl, propyl, butyl, or isopentyl, or cycloalkyl such as norbornyl, cyclohexyl, or adamantyl. A most preferred Ar group is phenyl, preferably substituted with 1, 2, or 3 groups selected from phenyl, chloro, bromo, methyl, methoxy, hydroxy, hydroxymethyl, 2-diethylaminoethoxy, methoxycarbonylmethyl, carboxy, carboxymethyl, ethoxycarbonyl, 2-carboxyethyl, 2-ethoxycarbonylethyl, NR4R5, and O(CH2)0-6NR4R5, wherein
R4 and R5 are as defined above. Another preferred Ar group is thiazolyl, for example, 2-thiazolyl, optionally substituted by phenyl, hydroxyphenyl, or alkoxyphenyl.
Additional preferred embodiments of the present invention include those in Examples 38, 41, 43, 51, 52, 53, 55, 74, 79, 84, and 85, infra. Even more preferred compounds are those displayed in Examples 59, 60, 77, 217, and 259 infra.
Compounds of Formula I wherein W is S, SO, or SO2 are especially useful as intermediates leading to compounds where W is NH, but such compounds also display inhibitory activity against cyclin-dependent kinases.
The compounds of the invention further comprise those of Formula II: 
wherein:
the dotted line represents an optional double bond of either trans or cis-stereochemistry;
W is NH, S, SO, or SO2;
Z is COOR7, CN, CHO, CH2QR7, CH2NHR7, CONHR7, or COR7;
R1 and R2 are independently selected from the group consisting of H, (CH2)nPh, (CH2)nheteroaryl, (CH2)nheterocycle, C1-C10 alkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, and C2-C10 alkynyl, wherein n is 0, 1, 2, or 3 and the (CH2)nPh, (CH2)nheteroaryl, alkyl, cycloalkyl, alkenyl, and alkynyl groups are optionally substituted by groups of NR4R5, N(O)R4R5, NR4R5R6Y, phenyl, substituted phenyl, hydroxy, alkoxy, phenoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, aldehyde, nitrile, nitro, heteroaryloxy, T(CH2)mQR4, C(O)T(CH2)mQR4, NHC(O)T(CH2)mQR4, or T(CH2)mCO2R4 wherein m is 1-6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, and Q is O, S, NR5, N(O)R5, or NR5R6Y;
R3 is H or alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)nPh, C3-C10 cycloalkyl, and heteroaryl, or R4 and R5 together with the nitrogen to which they are attached optionally form a ring having 3 to 7 carbon atoms and said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur;
R6 is alkyl;
Y is a halo counter-ion;
R7 is one of H, lower alkyl, or phenyl.
R8 and R9 independently are H, C1-C3alkyl, NR4R5, N(O)R4R5, NR4R5R68, hydroxy, alkoxy, thiol, thioalkyl, halo, COR4, CO2R4, CONR4R5, SO2NR4R5, SO3R4, PO3R4, CHO, CN, or NO2;
and the pharmaceutically acceptable salts thereof.
Preferably, compounds of Formula II have a trans double bond between C5 and C6, more preferably with R1 being phenyl, and even more preferably with both R1 being phenyl and R2 being alkyl or cycloalkyl.
Also preferred are compounds of Formula II wherein R8 and R9 both are hydrogen.
Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinal, morpholinyl, and the like.
Unless otherwise expressly stated, the following definitions are adhered to throughout this disclosure.
xe2x80x9cAlkylxe2x80x9d means a straight or branched hydrocarbon radical having from 1 to 10 carbon atoms (unless stated otherwise) and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, and the like.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo.
xe2x80x9cAlkenylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like.
xe2x80x9cAlkynylxe2x80x9d means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed xe2x80x9cheterocyclylxe2x80x9d, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine.
xe2x80x9cAlkoxyxe2x80x9d refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94CH3, and the like.
xe2x80x9cAlkanoylxe2x80x9d groups are alkyl linked through a carbonyl, ie, C1-C5xe2x80x94C(O)xe2x80x94. Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl.
xe2x80x9cAcylxe2x80x9d means an alkyl or aryl (Ar) group bonded through a carbonyl group, ie, Rxe2x80x94C(O)xe2x80x94. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like.
The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. xe2x80x9cSubstituted nitrogenxe2x80x9d means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced.
Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl.
Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like.
Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like.
Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like.
The terms xe2x80x9cArxe2x80x9d and xe2x80x9carylxe2x80x9d refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, pyrrole, pyrazole, imidazole, thiazole, and the like.
Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, hydroxy, xe2x80x94COOR7, amino of the formula xe2x80x94NR4R5, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4 and R5 are as described above, and R7 is alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl.
The compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
The compounds of Formula I and II are capable of further forming both pharmaceutically acceptable formulations comprising salts, including but not limited to acid addition and/or base salts, solvents and N-oxides of a compound of Formula I and/or II. This invention also provides pharmaceutical formulations comprising a compound of Formula I and/or II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. All of these forms are within the present invention.
Pharmaceutically acceptable acid addition salts of the compounds of Formula I and II include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, capryl ate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharmaceutical Science, 1977;66:1-19.
The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and allcine earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge, et al., supra.
The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
The compounds of the present invention are useful for treating cancer (for example, leukemia and cancer of the lung, breast, prostate, and skin such as melanoma) and other proliferative diseases including but not limited to psoriasis, HSV, HIV, restenosis, and atherosclerosis. To utilize a compound of the present invention to treat cancer, a patient having cancer is administered a therapeutically effective amount of a pharmaceutically acceptable composition comprising an invention compound.
A further embodiment of this invention is a method of treating subjects suffering from diseases caused by vascular smooth muscle cell proliferation. Compounds within the scope of the present invention effectively inhibit vascular smooth muscle cell proliferation and migration. The method entails inhibiting vascular smooth muscle proliferation, and/or migration by administering an effective amount of a compound of Formula I and/or II to a subject in need of treatment.
The compounds of the present invention can be formulated and administered in a wide variety of oral and parenteral dosage forms, including transdermal and rectal administration. It will be recognized to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I and/or II or a corresponding pharmaceutically acceptable salt or solvate of a compound of Formula I and/or II.
A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I and/or II together with a pharmaceutically acceptable carrier, diluent, or excipient therefor. For preparing pharmaceutical compositions with the compounds of the present invention, pharmacuetically acceptable carriers can be either a solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid such as talc or starch which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The formulations of this invention preferably contain from about 5% to about 70% or more of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. A preferred form for oral use are capsules, which include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogenously therein, as by stirring. The molten homogenous mixture is then poured into convenient size molds, allowed to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, and emulsions such as water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution, isotonic saline, 5% aqueous glucose, and the like. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water and mixing with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Waxes, polymers, microparticles, and the like can be utilized to prepare sustained-release dosage forms. Also, osmotic pumps can be employed to deliver the active compound uniformally over a prolonged period.
The pharmaceutical preparations of the invention are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The therapeutically effective dose of a compound of Formula I and/or Formula II will generally be from about 1 mg to about 100 mg/kg of body weight per day. Typical adult doses will be about 50 mg to about 800 mg per day. The quantity of active component in a unit dose preparation may be varied or adjusted from about 0.1 mg to about 500 mg, preferably about 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents. A subject in need of treatment with a compound of Formula I and/or II is administered a dosage of about 1 to about 500 mg per day, either singly or in multiple doses over a 24-hour period.
The compounds of the present invention are capable of binding to and inhibiting the activity of proteins having the ability to phosphorylate other proteins, such as cdks, PDGFr, FGFr, c-src, and EGFr-FL. Cdks form complexes with cyclins, and these complexes phosphorylate key proteins allowing cells to proceed through the cell cycle (Meijer L., Progress in Cell Cycle Research, 1995;1:351-363). The compounds of this invention inhibit this phosphorylation and therefore can be used as anti-proliferative agents for the treatment of cancer and/or restenosis and other proliferative diseases.
Because of their inhibitory activity against cdks and other kinases, the compounds of the present invention are also useful research tools for studying the mechanism of action of those kinases, both in vitro and in vivo.
While the forms of the invention herein constitute presently preferred embodiments, many others are possible. It is not intended herein to mention all of the possible equivalent forms or ramifications of the invention. It is understood that the terms used herein are merely descriptive rather than limiting, and those skilled in the art will realize that various changes may be made without departing from the spirit or scope of the invention.
The following compounds illustrate specific embodiments provided by the present invention, and the compounds listed below are among the preferred embodiments.
8-(3-Phenoxy-benzyl)2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Cyclopropyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Naphthalen-2-yl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethoxy-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Hex-2-ynyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methylsulfanyl-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,3-Dimethyl-butyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenethyl-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethyl-hexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-ylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Chloro-2-nitro-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Ethyl-oxetan-3-ylmethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(2-Methoxy-ethoxy)-ethyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,3-Pentafluoro-propyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(tetrahydro-furan-2-ylmethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-but-2-enyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(4tert-Butyl-phenoxy)-ethyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Ethyl-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenoxy-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-allyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-benzyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Butoxy-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2,2,2-trifluoro-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2-thiophen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzo[1,3]dioxol-5-ylmethyl-2-phenylamino-8H-pyrido[2,3-]pyrimidin-7-one;
8-Cyclohexylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethoxy-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-thiophen-2-ylmethyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-2-ylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenyl-allyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-3-ylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methoxy-propyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-bicyclo[2.2.1]hept-2-ylmethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(3-phenyl-prop-2-ynyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-3-oxo-butyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Bis-(4-fluoro-phenyl)-methyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoro-1,1-dimethyl-heptyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2,2,2-trifluoro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2,2,2-trichloro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,3-Dimethyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(tetrahydro-pyran-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-2-enyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-5-en-2-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,5-Dimethyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-sec-Butyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-1-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-5-methyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8(2,6-Dimethyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(5-Isopropyl-2-methyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-pent-2-ynyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2,2-diphenyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(4-Methoxy-phenyl)-ethyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1,2,3,4-tetrahydro-naphthalen-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1-p-tolyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Adamantan-2-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-but-3-ynyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Dicyclohexylmethyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(phenyl-o-tolyl-methyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(3,4-Dichloro-phenyl)-ethyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-hexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-2-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(2-Bromo-phenyl)ethyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methoxy-1-methyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-propyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Isopropyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Acenaphthen-1-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Oxo-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1,2,3,4-tetrahydro-naphthalen-1-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-heptyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-[phenyl-(2-trifluoromethyl-phenyl)-methyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1,1-Dioxo-tetrahydro-1-xcex46-thiophen-3-yl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Biphenyl-4-yl-ethyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzhydryl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(9H-xanthen-9-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Pentyl-prop-2-ynyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Octahydro-inden-5-yl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2-phenyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-tert-Butyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[3-Phenoxy-1-(2-phenoxy-ethyl)-propyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-propyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-prop-2-ynyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1-phenyl-heptyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclohexyl4-yl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-cyclohexyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Cyclohexyl-phenyl-methyl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1-phenyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(1-phenyl-prop-2-ynyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2-phenyl-[1,3]dioxan-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(7-Oxo-2-phenylamino-7H-pyrido[2,3-d]pyrimidin-8-yl)-propionitrile;
8-Cyclooctyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Decahydro-naphthalen-2-yl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(9H-Fluoren-9-yl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[4-(1,1-Dimethyl-propyl)cyclohexyl]-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-[2,2,2-trichloro-1-(4-fluoro-phenyl)-ethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-Phenylamino-8-(3,3,5-trimethyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenoxy-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-]pyrimidin-7-one;
8-(2-Cyclopropyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-]pyrimidin-7-one;
8-(2-Naphthalen-2-yl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethoxy-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Hex-2-ynyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methylsulfanyl-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,3-Dimethyl-butyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenethyl-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethyl-hexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-ylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(4Chloro-2-nitro-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Ethyl-oxetan-3-ylmethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-xe2x80x94pyrido[2,3-d]pyrimidin-7-one;
8-[2-(2-Methoxy-ethoxy)-ethyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,3-Pentafluoro-propyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(tetrahydro-furan-2-ylmethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-but-2-enyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-]pyrimidin-7-one;
8-[2-(4-tert-Butyl-phenoxy)-ethyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Ethyl-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenoxy-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-allyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-benzyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7one;
8-(2-Butoxy-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(2,2,2-trifluoro-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(2-thiophen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzo[1,3]dioxol-5-ylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(2-Ethoxy-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-thiophen-2-ylmethyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-2-ylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenyl-allyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-3-ylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methoxy-propyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-bicyclo[2.2.1]hept-2-ylmethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenyl-prop-2-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-3-oxo-butyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Bis-(4-fluoro-phenyl)-methyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoro-1,1-dimethyl-heptyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(2,2,2-trifluoro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(2,2,2-trichloro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,3-Dimethyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(tetrahydro-pyran-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-2-enyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-5-en-2-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,5-Dimethyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-sec-Butyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8Cyclohex-3-enyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-1-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-5-methyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Dimethyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(5-Isopropyl-2-methyl-cyclohexyl)-2-(4piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-pent-2-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2,2-diphenyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(4-Methoxy-phenyl)-ethyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1,2,3,4-tetrahydro-naphthalen-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1-p-tolyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Adamantan-2-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-but-3-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Dicyclohexylmethyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Phenyl-o-tolyl-methyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(3,4-Dichloro-phenyl)-ethyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-hexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-2-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(2-Bromo-phenyl)-ethyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methoxy-1-methyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-propyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Isopropyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Acenaphthen-1-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Oxo-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1,2,3,4-tetrahydro-naphthalen-1-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-heptyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Phenyl-(2-trifluoromethyl-phenyl)-methyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1,1-Dioxo-tetrahydro-xcex46-thiophen-3-yl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Biphenyl-4-yl-ethyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzhydryl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(9H-xanthen-9-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Pentyl-prop-2-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Octahydro-inden-5-yl)-2-(4piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-tert-Butyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[3-Phenoxy-1-(2-phenoxy-ethyl)-propyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-propyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-prop-2-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Phenyl-heptyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclohexyl-4-yl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-cyclohexyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Cyclohexyl-phenyl-methyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Phenyl-propyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Phenyl-prop-2-ynyl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenyl-[1,3]dioxan-5-yl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[7-Oxo-2-(4-piperidin-1-yl-phenylamino)-7H-pyrido[2,3-d]pyrimidin-8-yl]-propionitrile;
8-Cyclooctyl-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8Decahydro-naphthalen-2-yl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(9H-Fluoren-9-yl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[4-(1,1-Dimethyl-propyl)-cyclohexyl]-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-2-(4-piperidin-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-[2,2,2-trichloro-1-(4-fluoro-phenyl)-ethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Piperidin-1-yl-phenylamino)-8-(3,3,5-triethyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(3-phenoxy-benzyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Cyclopropyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-naphthalen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethoxy-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Hex-2-ynyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(4-methylsulfanyl-benzyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(4-methylsulfanyl-benzyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,3-Dimethyl-butyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-phenethyl-benzyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethyl-hexyl)-2-[4(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-ylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Chloro-2-nitro-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Ethyl-oxetan-3-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(2-Methoxy-ethoxy)-ethyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2,2,3,3,3-pentafluoro-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(tetrahydro-furan-2-ylmethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-but-2-enyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(4-tert-Butyl-phenoxy)-ethyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Ethyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-phenoxy-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-allyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-benzyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Butoxy-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2,2,2-trifluoro-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-thiophen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzo[1,3]dioxol-5-ylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethoxy-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-thiophen-2-ylmethyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-2-ylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(3-phenyl-allyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-3-ylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methoxy-propyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-bicyclo[2.2.1]hept-2-ylmethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(3-phenyl-prop-2-ynyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(2-Methyl-3-oxo-butyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Bis-(4-fluoro-phenyl)-methyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoro-1,1-dimethyl-heptyl)-2-[4(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2,2,2-trifluoro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2,2,2-trichloro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,3-Dimethyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(tetrahydro-pyran-4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-2-enyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-5-en-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-naphthalen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,5-Dimethyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-sec-Butyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-1-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-5-methyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-naphthalen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Dimethyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(5-Isopropyl-2-methyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-pent-2-ynyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2,2-diphenyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(4-Methoxy-phenyl)-ethyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1,2,3,4-tetrahydro-naphthalen-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-p-tolyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Adamantan-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-but-3-ynyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Dicyclohexylmethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(phenyl-o-tolyl-methyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(3,4-Dichloro-phenyl)-ethyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-hexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-2-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(2-Bromo-phenyl)-ethyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methoxy-1-methyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8(1-Methyl-2-phenyl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-propyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Isopropyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Acenaphthen-1-yl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-oxo-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1,2,3,4-tetrahydro-naphthalen-1-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-heptyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-[phenyl-(2-trifluoromethyl-phenyl)-methyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1,1-Dioxo-tetrahydro-xcex46-thiophen-3-yl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Bipheny-4-yl-ethyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzhydryl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(9H-xanthen-9-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-pentyl-prop-2-ynyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(octahydro-inden-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-phenyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-tert-Butyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-[3-phenoxy-1-(2-phenoxy-ethyl)-propyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-propyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-prop-2-ynyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-phenyl-heptyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclohexylyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-cyclohexyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Cyclohexyl-phenyl-methyl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-phenyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(1-phenyl-prop-2-ynyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2-phenyl-[1,3]dioxan-5-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl}-propionitrile;
8-Cyclooctyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Decahydro-naphthalen-2-yl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(9H-Fluoren-9-yl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[4-(1,1-Dimethyl-propyl)-cyclohexyl]-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-[2,2,2-trichloro-1-(4-fluoro-phenyl)-ethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-8-(3,3,5-trimethyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenoxy-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Cyclopropyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Naphthalen-2-yl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethoxy-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Hex-2-ynyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methylsulfanyl-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,3-Dimethyl-butyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenethyl-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethyl-hexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-ylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Chloro-2-nitro-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Ethyl-oxetan-3-ylmethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(2-Methoxy-ethoxy)-ethyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,3-Pentafluoro-propyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(tetrahydro-furan-2-ylmethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-but-2-enyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[2-(4-tert-Butyl-phenoxy)-ethyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Ethyl-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenoxy-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3]pyrimidin-7-one;
8-(2-Methyl-allyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-benzyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Butoxy-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(2,2,2-trifluoro-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(2-thiophen-2-yl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzo[1,3]dioxol-5-ylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Ethoxy-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-thiophen-2-ylmethyl-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-2-ylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenyl-allyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Furan-3-ylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methoxy-propyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-bicyclo[2.2.1]hept-2-ylmethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Phenyl-prop-2-ynyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-3-oxo-butyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Bis-(4-fluoro-phenyl)-methyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,2,3,3,4,4,5,5,6,6,7,7-Dodecafluoro-1,1-dimethyl-heptyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(2,2,2-trifluoro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(2,2,2-trichloro-1-phenyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,3-Dimethyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(tetrahydro-pyran4-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-2-enyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-5-en-2-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,5-Dimethyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-sec-Butyl-cyclohexyl)-2-(4-pyrazo-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohex-3-enyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-1-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Isopropyl-5-methyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Naphthalen-2-yl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2,6-Dimethyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(5-Isopropyl-2-methyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-pent-2-ynyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2,2-diphenyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(4-Methoxy-phenyl)-ethyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1,2,3,4-tetrahydro-naphthalen-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1-p-tolyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Adamantan-2-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-but-3-ynyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Dicyclohexylmethyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Phenyl-o-tolyl-methyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(3,4-Dichloro-phenyl)-ethyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-hexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Indan-2-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[1-(2-Bromo-phenyl)-ethyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methoxy-1-methyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-2-phenyl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-propyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Isopropyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Acenaphthen-1-yl-2-(4pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Oxo-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1,2,3,4-tetrahydro-naphthalen-1-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Methyl-heptyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[Phenyl-(2-trifluoromethyl-phenyl)-methyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1,1-Dioxo-tetrahydro-86-thiophen-3-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Biphenyl-4-yl-ethyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3-Methyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Benzhydryl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(9H-xanthen-9-yl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Pentyl-prop-2-ynyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Octahydro-inden-5-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(3,5-Dimethyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-tert-Butyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Methyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[3-Phenoxy-1-(2-phenoxy-ethyl)-propyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Cyclohexyl-propyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Ethyl-prop-2-ynyl)-2-(4pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(1-Phenyl-heptyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[(4-Methoxy-phenyl)-pyridin-2-yl-methyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclohexyl-4-yl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(4-Methyl-cyclohexyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Cyclohexyl-phenyl-methyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Phenyl-propyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(1-Phenyl-prop-2-ynyl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(2-Phenyl-[1,3]dioxan-5-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-[7-Oxo-2-(4-pyrazol-1-yl-phenylamino)-7H-pyrido[2,3-d]pyrimidin-8-yl]-propionitrile;
8-Cyclooctyl-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-(Decahydro-naphthalen-2-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8(9H-Fluoren-9-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-[4-(1,1-Dimethyl-propyl)-cyclohexyl]-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-( 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-2-(4-pyrazol-1-yl-phenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-[2,2,2-trichloro-1-(4-fluoro-phenyl)-ethyl]-8H-pyrido[2,3-d]pyrimidin-7-one;
2-(4-Pyrazol-1-yl-phenylamino)-8-(3,3,5-trimethyl-cyclohexyl)-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclopentyl-2-[4-(3-diethylamino-2-hydroxy-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclopentyl-2-[4-(2-hydroxy-3-morpholin-4-yl-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-[4-(3-diethylamino-2-hydroxy-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Cyclohexyl-2-[4-(2-hydroxy-3-morpholin-4-yl-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one;
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(3-diethylamino-2-hydroxy-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one; and
8-Bicyclo[2.2.1]hept-2-yl-2-[4-(2-hydroxy-3-morpholin-4-yl-propoxy)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one.
Compounds of Formulas I and II may be prepared according to the syntheses outlined in Schemes 1 through 9, infra. Although these schemes often indicate exact structures, those with ordinary skill in the art will appreciate that the methods apply widely to analogous compounds of Formula I and/or II, given appropriate consideration to protection and deprotection or reactive functional groups by methods standard to the art of organic chemistry. For example, hydroxy groups, in order to prevent unwanted side reactions, generally need to be converted to ethers or esters during chemical reactions at other sites in the molecule. The hydroxy protecting group is readily removed to provide the free hydroxy group. Amino groups and carboxylic acid groups are similarly derivatized to protect them against unwanted side reactions. Typical protecting groups and methods for attaching and cleaving them are described fully by Greene and Wuts in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, (2nd Ed., 1991), and McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973.
Scheme 1 describes a typical method for the preparation of the pyrido[2,3-d]pyrimidin-7(8H)-ones of the invention. The synthesis begins with commercially available (Aldrich) 4-chloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. Displacement of the 4-chloro group with an amine in a solvent such as tetrahydrofuran in the presence or absence of a tertiary amine such as triethylamine provides the corresponding 4-amino-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. The amine used can be anhydrous or in an aqueous solution as with methyl or ethyl amine. The use of aqueous ammonium hydroxide provides the corresponding primary amine at position 4. Oxidation of the methylthio group with an oxidant such as an oxaziridine in a solvent such as chloroform at room temperature provides the methyl sulfoxide derivative. Displacement of the sulfoxide with an amine results in formation of the corresponding 2,4-diamino-pyrimidine-5-carboxylic acid ethyl ester. The temperature required for the displacement depends upon the amine used. Aromatic, secondary, and tertiary amines usually require higher temperatures than primary aliphatic or benzyl amines. When aromatic amines such as aniline are used, the reaction is usually run with the amine as the solvent at high temperatures. The ester group is sequentially reduced to the alcohol, preferably with lithium aluminum hydride in tetrahydrofuran, and then oxidized to the aldehyde. While sodium dichromate can be used as the oxidant, superior results are obtained with manganese II oxide in chloroform.
The 2,4-di-amino-pyrimidine-5-carboxaldehydes can be reacted with either a stabilized phosphorane, a phosphonate ester in the presence of a base, or any alternative Wittig or Horner-Emmons reagent to provide the corresponding unsaturated ester. The resulting double bond can be trans, cis, or a mixture of both. For example, reaction of a 2,4-diamino-pyrimidine-5-carboxaldehyde with an excess amount of the stabilized phosphorane (carbethoxymethylene)triphenylphosphorane in tetrahydrofuran at reflux temperature gives mainly, or in some cases exclusively, the trans unsaturated ethyl ester. Upon treatment with base, ring closure occurs to give the desired pyrido[2,3-d]pyrimidin-7(8H)-one. This reaction can be carried out using a tertiary amine such as triethylamine or, preferably, N,N-diisopropylethyl amine as the solvent, with 1 to 10 equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene present. The reaction is carried out at elevated temperature, and is usually complete in 2 to 24 hours. Alternatively, the 2,4-diamino-pyrimidine-5-carboxaldehyde can be reacted with a phosphonate ester such as bis(2,2,2-trifluoroethyl)(methoxycarbonyl-methyl)-phosphonate using a strongly dissociated base (Tetrahedron Lett., 1983:4405) to give predominately, if not exclusively, the cis unsaturated ester. Upon treatment with base under the conditions discussed previously, ring closure occurs. 
Scheme 2 depicts the preparation of pyrido[2,3-d]pyrimidin-7(8H)-ones of the invention where R2 is H. The sequence of reactions is the same as Scheme 1, where the initial step uses ammonium hydroxide giving the 4-primary amino pyrimidine. The resultant pyrido[2,3-d]pyrimidin-7(8H)ones where R2 is equal to H can be alkylated at the 8-position by treatment with a base such as sodium hydride in a solvent such as dimethylformamide or tetrahydrofuran at temperatures ranging from 40xc2x0 C. to reflux, thus providing the corresponding pyrido[2,3-d]pyrimidin-7(8H)-ones where R2 is other than H. The advantage of the route shown in Scheme 2 is that it allows for several R2 analogs to be prepared from a common intermediate. The required aldehyde can also be obtained by reduction of the corresponding nitrile (J. Org. Chem., 1960;82:5711) with a reducing agent, preferably diisobutylaluminum hydride. 
A route that allows for the preparation of several analogs with various R1 groups from a common intermediate is shown in Scheme 3. The initial step is the same as in Scheme 1, but instead of oxidizing the methyl thio group, the ester is sequentially reduced and then oxidized using the conditions described in Scheme 1 to provide the corresponding 2-methylthio-4-amino-pyrimidine-5-carboxaldehyde. This aldehyde is converted to the corresponding unsaturated ester using the conditions described in Scheme 1. The methylthio group can be displaced directly with primary alkyl amines to give the pyrido[2,3d]pyrimidin-7-(8H)-ones of the invention where R1 is H or a primary alkyl group. The methylthio group can also be converted to the corresponding sulfoxide by treatment with an oxidizing agent, preferably an oxaziridine, in a solvent such as chloroform at room temperature. Alternatively, an oxidizing agent, such as m-chloroperbenzoic acid, can be used in excess to convert the methylthio derivative to the corresponding methyl sulfone. Upon treatment of these oxidized derivatives with an amine, usually with several equivalents of the amine at elevated temperatures in the case of aromatic or tertiary amines, pyrido[2,3-d]pyrimidin-7(8H)-ones of the invention with various R1 groups are obtained. In some cases a solvent such as tetrahydrofuran or dimethylsulfoxide can be used. 
The most convergent route to the compounds of the invention where X is O is via the synthesis of 2-methanesulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one which is depicted in Scheme 4. This key intermediate is prepared by the methods discussed in the previous schemes and is converted to the compounds of the invention by 2 routes, shown in Scheme 5. In the first, the methylthio group is converted to an amino group, in some cases via an oxidized intermediate. These derivatives are then alkylated at N8 to give the desired compounds. Alternatively, 2-methanesulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one is first alkylated at N8, then the methylthio group, or an oxidized derivative, is displaced by an amine. 
Scheme 6 describes a typical method for the preparation of the pyrido[2,3-d]pyrimidin-7(8H)-imines of the invention (X=NH). The synthesis begins with the 2,4-diamino-pyrimidine-5-carboxaldehyde previously described in Scheme 1. Reaction with diethyl cyanomethylphosphonate in the presence of a base, such as sodium hydride, in a solvent such as tetrahydrofuran, provides the corresponding unsaturated nitrile. This nitrile is then cyclized to give the pyrido[2,3-d]pyrimidin-7(8H)-imine under the same conditions used to prepare the pyrido[2,3-d]pyrimidin-7(8H)-ones of Scheme 1. Alternatively, the pyrimidine-5-carboxaldehyde can contain a methylthio group at C2. After formation of the unsaturated nitrile followed by ring closure, the methylthio group at C2 can be converted to an amino group by the methology previously mentioned. The pyrido[2,3-d]pyrimidin-7(8H)-imines can also be converted to the pyrido[2,3-d]pyrimidin-7(8H)-ones by direct hydrolysis with concentrated acid, such as hydrochloric acid, at elevated temperatures. A milder method can also be used where the imine is first acylated with acetic anhydride. The hydrolysis of this acyl intermediate to the 7-one occurs under shorter reaction time and lower reaction temperatures. 
As shown in Scheme 7, those compounds where there is no double bond between C5 and C6 can be prepared by direct reduction of the double bond for those cases where X is O. Alternatively, a more preferred route is to reduce the double bond of the precursor unsaturated ester. This can be accomplished with a metal catalyst, such as palladium, in the presence of hydrogen under pressure. This saturated ester is then cyclized using the conditions discussed previously. Due to the propensity of the imine or nitrile group to be reduced under the conditions used to reduce the carbon-carbon double bond, a different route is required to prepare the compounds of the invention without a double bond at C5xe2x80x94C6 for those cases where X is NH. The saturated ester is hydrolyzed to the acid and then converted to the primary amide, by activation of the carboxylate with an acid chloride or N,N-carbonyldiimidazole, followed by treatment with ammonia gas or aqueous ammonium hydroxide. The primary amide is dehydrated to the corresponding nitrile with a reagent such as phosphorous pentoxide. This saturated nitrile is then cyclized using the conditions described previously. 
It should be noted that while the routes depicted in the earlier schemes showed the preparation of the pyrido[2,3-d]pyrimidin-7(8H)-ones of the invention where R3 is H, these routes can be readily modified to prepare compounds where R3 is lower alkyl, as shown in Scheme 8. Treatment with base provides compounds of the invention where X is O and R3 is lower alkyl. Alternatively, these same reactions can be carried out on the 2-methylthio-4-amino-pyrimidine-5-carboxaldehyde and, after cyclization, the 2-methylthio group can be converted to the corresponding amine. Suitable modification of Scheme 6 would lead to the preparation of the pyrido[2,3-d]pyrimidin-7(8H)-imines of the invention where R3 is lower alkyl. 
Additional 2,4-diaminopyrimidines of the invention can be prepared as shown in Scheme 9. For example, those analogs where Z is CH2OH are prepared by reduction of the ester with a reducing agent such as an excess of diisobutylaluminum hydride in a solvent such as tetrahydrofuran or chloroform. Subsequent oxidation with an oxidizing agent such as manganese oxide, or Swem""s conditions, provides the compound where Z is CHO. Compounds where Z is COOR7 or CONHR7 can be obtained from the compound where Z is COOH. Activation of the carboxylate with an acid chloride or 1,1-carbonyldiimidazole, followed by addition of an alcohol of formula R7OH or an amine of formula R7NH2, would provide those compounds where Z is COOR7 and CONHR7, respectively. 